PROJECT SUMMARY/ABSTRACT Dr. Miocinovic is establishing herself as a physician-scientist conducting patient-centered research in the field of movement disorder electrophysiology and deep brain stimulation (DBS). This K23 will provide Dr. Miocinovic with the support necessary to accomplish the following goals: (1) to gain knowledge in the use of advanced imaging techniques to visualize neural pathways in the human brain; (2) to become proficient in acquisition and analysis of intraoperative electrophysiology recordings; (3) to learn skills necessary to translate novel research methods into clinical practice; and (4) to develop an independent research career. To achieve these goals, Dr. Miocinovic has assembled a mentoring team consisting of a primary mentor: Dr. Philip Starr (a functional neurosurgeon with expertise in human movement disorders electrophysiology); two co-mentors: Dr. Jill Ostrem (a movement disorders neurologist with expertise in DBS management and clinical trials), and Dr. Pratik Mukherjee (a neuroradiologist with expertise in MRI tractography), and two collaborators: Dr. Cameron McIntyre (a biomedical engineer with expertise in computational modeling of DBS), and Dr. Alastair Martin (a medical physicist with expertise in MRI technology). The goal of the proposed research project is to understand which neural pathways are directly activated by DBS applied to the subthalamic area of patients with Parkinson's disease. This will be accomplished by measuring stimulation evoked potentials using a high- resolution subdural cortical recording strip, visualizing specific fiber pathways using MRI tractography and estimating the spread of stimulation effects using 3-dimensional biophysical computational models. The main focus is on the cortico-subthalamic hyperdirect pathway because of its potential importance in DBS therapeutic mechanism and accessibility for direct physiologic recordings. Aim 1: Dr. Miocinovic will determine how DBS parameter adjustments affect activation of the hyperdirect pathway using intraoperative cortical recordings. Aim 2: Dr. Miocinovic will validate the use of tractography-based, patient-specific computational models to predict preferential activation of the hyperdirect pathway. The ultimate goal of this project is to apply convergent methods to identify a target for subthalamic DBS in Parkinson's disease that achieves optimal therapeutic benefit. The proposed research is innovative because it utilizes electrocorticography to validate the use of tractography-based, patient-specific models for DBS parameter selection. Results from the proposed research will make significant contributions to our understanding of DBS mechanisms and advance methods for patient-specific DBS parameter selection, thus moving away from the trial-and-error approach currently used in clinical practice. Dr. Miocinovic's K23 training will prepare her to compete for R01 funding and translate these novel methods into clinical practice.